1. Field of the Invention
The present invention relates to methods for detecting, identifying, isolating, and selectively labelling and targeting TH1 lymphocytes and, more particularly, to such methods which use the presence of LAG-3 protein on the surface thereof as markers for the identity of TH1 lymphocytes. The present invention also related to methods of treating infectious diseases, cancer, Th1-mediated diseases and disorders associated with an imbalance of Th1 and Th2 cells.
2. Description of the Background Art
The lymphocyte activation gene (LAG-3) is a member of the immunoglobulin superfamily, that is selectively transcribed in human activated T (both CD4.sup.+ and CD8.sup.+) and NK cells (Triebel et al, 1990; see also WO91-110682). The sequence data, the compared exon/intron organization, and the chromosomal localization revealed that LAG-3 is closely related to CD4 (Baixeras et al, 1992). The close relationship between LAG-3 and CD4 was further strengthened by the demonstration that both share the same ligand, i.e., MHC class II molecules (Baixeras et al, 1992). However, in contrast to CD4, LAG-3 does not bind the human immunodeficiency virus gp120 (Baixeras et al, 1992). In vivo, LAG-3 expression was neither found in primary lymphoid organs, such as spleen, mucosa-associated lymphoid tissue or normal lymph nodes. However, it was readily detected in inflamed tonsils, or lymph nodes with follicular hyperplasia, supporting the view that even in vivo LAG-3 is expressed following activation (Huard et al, 1994A) The physiological role of encoded LAG-3 protein is still unclear. Antigen-specific stimulation of T-cell clones in the presence of anti-LAG-3 monoclonal antibody (mAb) led to increased thymidine incorporation, higher expression of activation marker CD25 and enhanced cytokine production (Huard et al, 1994B). Accordingly, addition of a soluble recombinant form of LAG-3 inhibited antigen-specific T-cell proliferation, suggesting a regulatory role of LAG-3 in CD4.sup.+ T-lymphocyte activation (Huard, 1995).
Studies of both murine and human CD4.sup.+ T-cell clones have shown that CD4.sup.+ T helper (Th) cells comprise functionally heterogenous populations based on their profile or cytokine production (Mosmann et al, 1986; Del Prete et al, 1991). Th1 cells produce interleukin (IL)-2, interferon (IFN)-.gamma. and tumor necrosis factor (TNF)-.beta., whereas Th2 cells produce IL-4 and IL-5. In the absence of a prominent differentiation of Th1 or Th2 cells, the large majority of CD4.sup.+ T-cells produce both Th1- and Th2-type cytokines (i.e., Th0 cells) (Mosmann et al, 1986; Del Prete et al, 1991; Sher et al, 1992; Romagnani, S., 1994). Recently, we have shown that human Th1 and Th2 clones not only exhibit different functional properties but also show differential expression of CD30 (Del Prete et al, 1995A), an activation marker belonging to the TNF receptor family (Smith et al, 1990).
It has been suggested that Th1 cells contribute to the pathogenesis of organ-specific autoimmune diseases while Th2 cells prevents them (Liblau et al, 1995). Thus, it would be useful to have a simple way to identify and isolate Th1 cells to the exclusion of Th2 cells.
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